Non-enzymatic glycation of macromolecules such as proteins and certain phospholipids (phosphatidylethanolamine and phosphatidylserine) appears to play an important role in the evolution of diabetic complications. With the discovery of fructosamine-3-kinase (FN3K) (Szwergold, et al. (1997) Diabetes 46:108A; Delpierre, et al. (2000) Diabetes 49:1627-34; Szwergold, et al. (2001) Diabetes 50:2139-47) and evidence that this kinase functions as a deglycating enzyme (Delpierre, et al. (2002) Biochem. J. 365:801-8; Delpierre, et al. (2004) J. Biol. Chem. 279:27613-20; Szwergold, et al. (2002) Proceeding of the 7th International Symposium on Maillard Reaction, vol. 1245C, Amsterdam/New York: Elsevier, p. 143-52) it is evident that, while the non-enzymatic glycation process is unavoidable (especially in homeothermic animals), it also appears to be counteracted in vivo by active deglycation mechanisms. Thus, the classical “nonenzymatic glycation” hypothesis of diabetic complications (Ceriello (1999) Diab. Nutr. Met. Clin. Exp. 12:42-6; van Boekel (1991) Mol. Biol. Rep. 15:57-64) has been modified to a “glycation/deglycation” hypothesis (Szwergold, et al. (2002) supra).
While data concerning the deglycating function of FN3K is accumulating, it is also becoming clear that FN3K alone cannot be the sole deglycating mechanism (Szwergold, et al. (2001) supra; Szwergold (2005a) Med. Hypotheses 65:337-48; Szwergold, et al. (2005b) Ann. NY Acad. Sci. 1043:845-64). It appears likely that FN3K-mediated deglycation of ketosamines is complemented by another process that lowers the concentration of aldosamines (A.K.A. Schiff bases) (Szwergold (2005a) supra; Szwergold, et al. (2005b) supra; Szwergold (2005c) BBRC 336:36-41). These data suggest that this FN3K-independent mechanism operates by the removal of the carbohydrate moiety from macromolecule-bound aldosamines by one or several of the numerous low molecular weight intracellular nucleophiles through a process of transglycation (Scheme 1).

It is not clear which nucleophiles are most relevant to transglycation in vivo. It has been suggested that, due to its ubiquity and high concentrations, glutathione may be the most important general transglycating agent (Szwergold (2005a) supra; Szwergold (2005b) supra) complemented in some tissues by peptides such as carnosine and anserine in the skeletal muscle (Szwergold (2005c) supra) and/or free amino acids, sulfhydryls and polyamines in other tissues (Szwergold 2005a).